Cubicin News

WARNINGS

Clostridium difficile –associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including CUBICIN, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon, leading to overgrowth of C. difficile.

C. difficile produces toxins A and B, which contribute to the development of CDAD. Hypertoxin-producing strains of C. difficile cause increased morbidity and mortality, since these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary because CDAD has been reported to occur over 2 months after the administration of antibacterial agents.

If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.

PRECAUTIONS

General

The use of antibiotics may promote the selection of non-susceptible organisms. Should superinfection occur during therapy, appropriate measures should be taken.

Prescribing CUBICIN in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

Information for Patients

Diarrhea is a common problem caused by antibiotics that usually ends when the antibiotic is discontinued. Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as 2 or more months after having received the last dose of the antibiotic. If this occurs, patients should contact their physician as soon as possible.

Persisting or Relapsing S. aureus Infection

Patients with persisting or relapsing S. aureus infection or poor clinical response should have repeat blood cultures. If a culture is positive for S. aureus, MIC susceptibility testing of the isolate should be performed using a standardized procedure, as well as diagnostic evaluation to rule out sequestered foci of infection. Appropriate surgical intervention (e.g., debridement, removal of prosthetic devices, valve replacement surgery) and/or consideration of a change in antibiotic regimen may be required.

Failure of treatment due to persisting or relapsing S. aureus infections was assessed by the Adjudication Committee in 19/120 (15.8%) CUBICIN-treated patients (12 with MRSA and 7 with MSSA) and 11/115 (9.6%) comparator-treated patients (9 with MRSA treated with vancomycin and 2 with MSSA treated with anti-staphylococcal semi-synthetic penicillin). Among all failures, 6 CUBICIN-treated patients and 1 vancomycin-treated patient developed increasing MICs (reduced susceptibility) by central laboratory testing on or following therapy. Most patients who failed due to persisting or relapsing S. aureus infection had deep-seated infection and did not receive necessary surgical intervention (see CLINICAL STUDIES).

Skeletal Muscle

In a Phase 1 study examining doses up to 12 mg/kg q24h of CUBICIN for 14 days, no skeletal muscle effects or CPK elevations were observed.

In Phase 3 cSSSI trials of CUBICIN at a dose of 4 mg/kg, elevations in CPK were reported as clinical adverse events in 15/534 (2.8%) CUBICIN-treated patients, compared with 10/558 (1.8%) comparator-treated patients.

In the S. aureus bacteremia/endocarditis trial, at a dose of 6 mg/kg, elevations in CPK were reported as clinical adverse events in 8/120 (6.7%) CUBICIN-treated patients compared with 1/116 (<1%) comparator-treated patients. There were a total of 11 patients who experienced CPK elevations to above 500 U/L. Of these 11 patients, 4 had prior or concomitant treatment with an HMG-CoA reductase inhibitor.

Patients receiving CUBICIN should be monitored for the development of muscle pain or weakness, particularly of the distal extremities. In patients who receive CUBICIN, CPK levels should be monitored weekly, and more frequently in patients who received recent prior or concomitant therapy with an HMG-CoA reductase inhibitor. In patients with renal insufficiency, both renal function and CPK should be monitored more frequently. Patients who develop unexplained elevations in CPK while receiving CUBICIN should be monitored more frequently. In the cSSSI studies, among patients with abnormal CPK (>500 U/L) at baseline, 2/19 (10.5%) treated with CUBICIN and 4/24 (16.7%) treated with comparator developed further increases in CPK while on therapy. In this same population, no patients developed myopathy. CUBICIN-treated patients with baseline CPK >500 U/L (N=19) did not experience an increased incidence of CPK elevations or myopathy relative to those treated with comparator (N=24). In the S. aureus bacteremia/endocarditis study, 3 (2.6%) CUBICIN-treated patients, including 1 with trauma associated with a heroin overdose and 1 with spinal cord compression, had an elevation in CPK >500 U/L with associated musculoskeletal symptoms. None of the patients in the comparator group had an elevation in CPK >500 U/L with associated musculoskeletal symptoms.

CUBICIN should be discontinued in patients with unexplained signs and symptoms of myopathy in conjunction with CPK elevation >1,000 U/L (~5X ULN), or in patients without reported symptoms who have marked elevations in CPK >2,000 U/L (≥10X ULN). In addition, consideration should be given to temporarily suspending agents associated with rhabdomyolysis, such as HMG-CoA reductase inhibitors, in patients receiving CUBICIN.

In a Phase 1 study examining doses up to 12 mg/kg q24h of CUBICIN for 14 days, no evidence of nerve conduction deficits or symptoms of peripheral neuropathy was observed. In a small number of patients in Phase 1 and Phase 2 studies at doses up to 6 mg/kg, administration of CUBICIN was associated with decreases in nerve conduction velocity and with adverse events (e.g., paresthesias, Bell’s palsy) possibly reflective of peripheral or cranial neuropathy. Nerve conduction deficits were also detected in a similar number of comparator subjects in these studies. In Phase 3 cSSSI and community-acquired pneumonia (CAP) studies, 7/989 (0.7%) CUBICIN-treated patients and 7/1,018 (0.7%) comparator-treated patients experienced paresthesias. New or worsening peripheral neuropathy was not diagnosed in any of these patients. In the S. aureus bacteremia/endocarditis trial, a total of 11/120 (9.2%) CUBICIN-treated patients had treatment-emergent adverse events related to the peripheral nervous system. All of the events were classified as mild to moderate in severity; most were of short duration and resolved during continued treatment with CUBICIN or were likely due to an alternative etiology. In animals, effects of CUBICIN on peripheral nerve were observed (see ANIMAL PHARMACOLOGY). Therefore, physicians should be alert to the possibility of signs and symptoms of neuropathy in patients receiving CUBICIN.

Drug Interactions

Warfarin

Concomitant administration of CUBICIN (6 mg/kg q24h for 5 days) and warfarin (25 mg single oral dose) had no significant effect on the pharmacokinetics of either drug, and the INR was not significantly altered. As experience with the concomitant administration of CUBICIN and warfarin is limited, anticoagulant activity in patients receiving CUBICIN and warfarin should be monitored for the first several days after initiating therapy with CUBICIN (see CLINICAL PHARMACOLOGY, Drug-Drug Interactions).

HMG-CoA Reductase Inhibitors

Inhibitors of HMG-CoA reductase may cause myopathy, which is manifested as muscle pain or weakness associated with elevated levels of CPK. There were no reports of skeletal myopathy in a placebo-controlled Phase 1 trial in which 10 healthy subjects on stable simvastatin therapy were treated concurrently with CUBICIN (4 mg/kg q24h) for 14 days. In the Phase 3 S. aureus bacteremia/endocarditis trial, 5/22 CUBICIN-treated patients who received prior or concomitant therapy with an HMG-CoA reductase inhibitor developed CPK elevations >500 U/L. Experience with coadministration of HMG-CoA reductase inhibitors and CUBICIN in patients is limited; therefore, consideration should be given to temporarily suspending use of HMG-CoA reductase inhibitors in patients receiving CUBICIN (see ADVERSE REACTIONS, Post-Marketing Experience).

Drug-Laboratory Test Interactions

Clinically relevant plasma levels of daptomycin have been observed to cause a significant concentration-dependent false prolongation of prothrombin time (PT) and elevation of International Normalized Ratio (INR) when certain recombinant thromboplastin reagents are utilized for the assay. The possibility of an erroneously elevated PT/INR result due to interaction with a recombinant thromboplastin reagent may be minimized by drawing specimens for PT or INR testing near the time of trough plasma concentrations of daptomycin. However, sufficient daptomycin levels may be present at trough to cause interaction.

If confronted with an abnormally high PT/INR result in a patient being treated with CUBICIN, it is recommended that clinicians:

Repeat the assessment of PT/INR, requesting that the specimen be drawn just prior to the next CUBICIN dose (i.e., at trough concentration). If the PT/INR value drawn at trough remains substantially elevated over what would otherwise be expected, consider evaluating PT/INR utilizing an alternative method.

Evaluate for other causes of abnormally elevated PT/INR results.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term carcinogenicity studies in animals have not been conducted to evaluate the carcinogenic potential of daptomycin. However, neither mutagenic nor clastogenic potential was found in a battery of genotoxicity tests, including the Ames assay, a mammalian cell gene mutation assay, a test for chromosomal aberrations in Chinese hamster ovary cells, an in vivo micronucleus assay, an in vitro DNA repair assay, and an in vivo sister chromatid exchange assay in Chinese hamsters.

Daptomycin did not affect the fertility or reproductive performance of male and female rats when administered intravenously at doses up to 150 mg/kg/day, which is approximately 9 times the estimated human exposure level based upon AUCs.

Pregnancy

Teratogenic Effects: Pregnancy Category B

Reproductive and teratology studies performed in rats and rabbits at doses of up to 75 mg/kg, 2 and 4 times the 6 mg/kg human dose, respectively, on a body surface area basis, have revealed no evidence of harm to the fetus due to daptomycin. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Nursing Mothers

It is not known if daptomycin is excreted in human milk. Caution should be exercised when CUBICIN is administered to nursing women.

Pediatric Use

Safety and efficacy of CUBICIN in patients under the age of 18 have not been established.

Geriatric Use

Of the 534 patients treated with CUBICIN in Phase 3 controlled clinical trials of cSSSI, 27.0% were 65 years of age or older and 12.4% were 75 years of age or older. Of the 120 patients treated with CUBICIN in the Phase 3 controlled clinical trial of S. aureus bacteremia/endocarditis, 25.0% were 65 years of age or older and 15.8% were 75 years of age or older. In Phase 3 clinical studies of cSSSI and S. aureus bacteremia/endocarditis, lower clinical success rates were seen in patients ≥65 years of age compared with those <65 years of age. In addition, treatment-emergent adverse events were more common in patients ≥65 years old than in patients <65 years of age.